Ophthalmic Pharmaceutical Compositions Based on Amino Acids and Sodium Hyaluronate

ABSTRACT

This invention relates to ophthalmic wound-healing pharmaceutical compositions based on amino acids and sodium hyaluronate.

FIELD OF INVENTION

The present invention relates to ophthalmic pharmaceutical compositions,based on amino acids and sodium hyaluronate, with a protective andregenerating action on the corneal epithelial cells.

PRIOR ART

No cure for hypolacrimation (dry eye) has yet been found. Dry eyesyndrome is treated with eyedrops or gels (artificial tears) having acleansing, lubricant and disinfecting action, which possess thechemico-physical characteristics of natural tears.

Artificial tears are fairly dense preparations, designed to remain inthe eye at length and prevent rapid dilation.

These products considerably reduce the quality of vision afteradministration, and do not perform any wound-healing action.

Eye surgery designed to correct visual defects and remove cataracts isbecoming increasingly common. These operations do not usually requirestitches, but the wounds take some time to heal.

No wound-healing agents exist which promote rapid healing of cornealulcerations, wounds and lesions of post-operative, pathological,traumatic or parasurgical origin.

Consequently, treatment usually involves administering topicalpreparations (eyedrops, ointments or artificial tears) with anantibiotic and anti-inflammatory activity.

There is therefore a need for new preparations which perform aregenerating action at epithelial level, and promote cornealre-epithelialisation and rapid healing.

DESCRIPTION OF THE INVENTION

It has now been found that the combination of some amino acids withsodium hyaluronate is particularly effective in promoting the process ofreconstitution of the corneal epithelium and the stromal tissue in thecase of pathological, traumatic, surgical or parasurgical corneallesions.

The invention therefore relates to ophthalmic pharmaceuticalcompositions containing, as active ingredient, a combination of:

a) glycine and proline;

b) sodium hyaluronate; and possibly

c) lysine and leucine.

More particularly, the compositions according to the invention containglycine, L-proline and sodium hyaluronate, and possibly L-lysine in theform of hydrochloride and L-leucine.

The compositions according to the invention have a surprising effect asadjuvants: they aid regeneration of the epithelial microvilli and induceand accelerate corneal re-epithelialisation after eye surgery.

The compositions according to the invention will therefore be used totreat:

-   -   slight, moderate or serious alterations of the tear film: the        regeneration effect on the epithelial microvilli, which        represent the fundamental substrate for effective restoration of        the glycocalyx and consequently the tear film, drastically        reduces the typical symptoms of dry eye.    -   patients who undergo laser treatments (PRK): the reduction in        post-operative re-epithelialisation time prevents the appearance        of haze and dry eye syndrome which are typical of the first few        months after surgery;    -   relapsing and/or persistent corneal ulcers: the lasting        re-epithelialisation effect prevents relapses and allows        complete re-epithelialisation;    -   cataract removal surgery, phacoemulsification: the rapid healing        effect on the corneal tunnel significantly reduces the        discomfort felt by the patient.

The compositions according to the invention will be applied to the eye4-6 times a day, for a maximum of 3 months.

The compositions according to the invention will contain the variousactive ingredients within the following percentage ranges by weight:

-   -   glycine 0.01 to 0.5%;    -   L-proline: 0.09 to 0.06%;    -   sodium hyaluronate: 0.5 to 0.1% and possibly    -   L-lysine hydrochloride: 0.01 to 0.02%;    -   L-leucine: 0.02 to 0.005%.

According to a preferred aspect, the compositions according to theinvention will contain the various active ingredients in the followingpercentages by weight:

-   -   glycine: 0.1%    -   L-proline: 0.075%;    -   sodium hyaluronate: 0.3%;

and possibly

-   -   L-lysine hydrochloride: 0.014;    -   L-leucine: 0.011%.

The following is an example of a formulation according to the invention.

EXAMPLE

Eyedrop formulation Grams per INGREDIENTS unit dose Sodium hyaluronate0.3000 L-Proline 0.0752 Glycine 0.1000 L-Lysine HCl 0.0140 L-Leucine0.0108 Sodium chloride 0.9000 Distilled water to 100.0 mL

Preparation

30 kg of purified water is mixed with L-proline, glycine, lysine HCl,L-leucine and sodium chloride, and stirred until all the components havecompletely dissolved.

Sodium hyaluronate is added separately to 100 kg of purified water, andstirred until the component has completely dissolved.

The two solutions are combined and made up to the final volume of 144litres with purified water, checking that the pH value is between 6 and7, and adjusting with citric acid or sodium bicarbonate if necessary.

Finally, the solution is filtered through an 0.22 μm filter understerile conditions and placed in a container.

Pharmacological Trial

The protective and regenerative efficacy of the artificial tearsaccording to the invention in reconstituting the corneal epithelium andstromal tissue in the case of pathological, traumatic, surgical, orparasurgical corneal lesions was investigated.

300 eyes of 200 patients were examined:

-   -   100 eyes of 50 patients suffering from slight, moderate or        serious alterations of the tear film (Group A);    -   80 eyes of 40 patients who underwent laser surgery (PRK) (Group        B);    -   20 eyes of 20 patients suffering from relapsing and/or        persistent corneal ulcers (Group C);    -   84 eyes of 84 patients who underwent cataract removal surgery,        namely phacoemulsification with IOL implantation (Group D).

Cytomorphological study of the eye surface with confocal scanningelectron microscopy (SEM) made it possible to analyse the histologicalmodifications of the epithelial cells, and especially the microvilli.The Schimer test and BUT were used for the staging of the teardeficiency.

Regeneration of the epithelial microvilli, the fundamental substrate foreffective restoration of the glycocalyx, and consequently the tear film,was observed in Group A. The patients already perceived a noticeablebenefit after 10 days of treatment, with a drastic reduction in thetypical symptoms of dry eye.

In Group B, the post-operative re-epithelialisation time was shortenedfrom the usual 4-6 days to 2-3 days, and the administration ofartificial tears, even after re-epithelialisation was complete, provedto prevent the appearance of haze and the dry eye syndrome typical ofthe first few months after surgery.

In Group C, re-epithelialisation and stability of the epithelium wereobtained, without relapses, and where the ulcer had been already presentfor several weeks, complete re-epithelialisation was achieved.

Early healing of the corneal tunnel, with a definite reduction in thetypical discomfort felt by the patient, was observed in Group D only afew days after the cataract operation.

1-5. (canceled)
 6. An ophthalmic pharmaceutical composition comprisingas active ingredient a combination of: a) glycine and proline; and b)sodium hyaluronate.
 7. The ophthalmic pharmaceutical composition ofclaim 6, the composition further comprising as active ingredient: c)lysine and leucine.
 8. The ophthalmic pharmaceutical composition ofclaim 6, wherein proline is L-proline, and wherein glycine, L-prolineand sodium hyaluronate are comprised within the following percentageranges by weight: glycine 0.01 to 0.5%; L-proline: 0.09 to 0.06%, andsodium hyaluronate; 0.5 to 0.1%.
 9. The ophthalmic pharmaceuticalcomposition of claim 7, wherein lysine is L-lysine, leucine is L-leucineand wherein L-lysine and L-leucine are comprised within the followingpercentage ranges by weight: L-lysine hydrochloride: 0.01 to 0.02%; andL-leucine: 0.02 to 0.005%.
 10. The ophthalmic pharmaceutical compositionof claim 6, wherein proline is L-proline, and wherein glycine, L-prolineand sodium hyaluronate have the following percentage ranges by weight:glycine: 0.1% L-proline: 0.075%; and sodium hyaluronate: 0.3%.
 11. Theophthalmic pharmaceutical composition of claim 7, wherein lysine isL-lysine, leucine is L-leucine and wherein L-lysine and L-leucine havethe following percentage ranges by weight: L-lysine hydrochloride:0.014%, and L-leucine: 0.011%
 12. The ophthalmic pharmaceuticalcomposition of claim 6, wherein the composition is in form of eyedrops,artificial tears, ointment or gel.
 13. The ophthalmic pharmaceuticalcomposition of claim 7, wherein the composition is in form of eyedrops,artificial tears, ointment or gel.
 14. The ophthalmic pharmaceuticalcomposition of claim 8, wherein the composition is in form of eyedrops,artificial tears, ointment or gel.
 15. The ophthalmic pharmaceuticalcomposition of claim 9, wherein the composition is in form of eyedrops,artificial tears, ointment or gel
 16. The ophthalmic pharmaceuticalcomposition of claim 10 wherein the composition is in form of eyedrops,artificial tears, ointment or gel.
 17. The ophthalmic pharmaceuticalcomposition of claim 11 wherein the composition is in form of eyedrops,artificial tears, ointment or gel.
 18. A method to treat a cornealulceration in a patient, the method comprising administering to thepatient the ophthalmic pharmaceutical composition of claim
 6. 19. Amethod to treat a corneal ulceration in a patient, the method comprisingadministering to the patient the ophthalmic pharmaceutical compositionof claim
 7. 20. A method to treat a lesion of pathological, traumatic,surgical, or parasurgical origin in a patient, the method comprisingadministering to the patient the ophthalmic pharmaceutical compositionof claim
 6. 21. A method to treat a lesion of pathological, traumatic,surgical, or parasurgical origin in a patient, the method comprisingadministering to the patient the ophthalmic pharmaceutical compositionof claim
 7. 22. A method to treat symptoms of dry eye in a patient, themethod comprising administering to the patient the ophthalmicpharmaceutical composition of claim
 6. 23. A method to treat symptoms ofdry eye in a patient, the method comprising administering to the patientthe ophthalmic pharmaceutical composition of claim 7.